ES2319777T3 - TREATMENT OF CARCINOMA OF RENAL CELLS. - Google Patents

Abstract

The use of pegylated interferon alfa-2b for the manufacture of a medicament for the treatment of a patient who has renal cell carcinoma, wherein said medicament has to be administered in a therapeutically effective dose of pegylated interferon alfa-2b once per week for a period of at least 12 months, in which the pegylated interferon alfa-2b comprises polyethylene glycol having an average molecular weight of 12,000 and the therapeutically effective dose of about 4.5 µg / kg to about 9.0 µg / kg .

Description

Treatment of renal cell carcinoma.

Background of the invention

This invention relates to an improved therapy. to treat patients who have renal cell carcinoma ("RCC") by administering a therapeutically effective dose of pegylated alpha interferon for sufficient time to get at least a partial tumor response.

Metastatic renal cell carcinomas they are generally resistant to chemotherapy, with single agents or in combination. Greater success has been observed with immunotherapy, particularly with the use of interleukin-2 ("IL-2"). IL-2 therapy Intravenous high dose has resulted in tumor responses objective in approximately 14% of patients, some with prolonged durability. The administration of High dose IL-2 is associated with the syndrome of capillary hyperpermeability, which results in hypotension and reduced organ perfusion that can be serious and in some cases mortal. These toxicities have generally suppressed the use of IL-2 to a highly selected group of patients administered by doctors who are considerably experienced in his administration. The use of dose administered guidelines lower and subcutaneous (SC) route of IL-2 alone or in combination with other biological agents, which include interferon-?, has been explored in an effort of developing a therapy that can be applied more widely to this sickness. For example, Atzpodien, J., and others described in J. Clin Oncol., 1995, Volume 13, pages 497-501 that the combination treatment of subcutaneous administration ("SC") and lower dose interferon guidelines alpha-2b and interleukin-2 SC a patients with progressive metastatic RCC produced tumor response With less toxicity. It should be noted that the response rates are low and that interferon injections were required alpha-2b 5 million IU / m2 three times a week ("TIW") to achieve these results.

In addition, interferon alfa-2b It has many side effects that a substantial number of patients find unacceptable and patient compliance with TIW injections of interferon alfa-2b has been Become a problem. WO 98/48840 describes polyethylene glycol-interferon alpha conjugates that they are useful in methods to treat viral infections, particularly hepatitis Con, but does not describe the use of these conjugates to treat RCC. Consequently, there is a need for an improved therapy to treat patients who have RCC.

Summary of the invention

The present invention provides a method for treat a patient who has renal cell carcinoma that comprises administering to a patient of this type a dose therapeutically effective pegylated interferon alpha during a sufficient period of time to produce at least one response partial tumor

The present invention also provides a method to treat a patient who has metastatic carcinoma of renal cells comprising administering to said patient a effective amount of pegylated interferon-alpha a once a week for a period of time sufficient to produce at least a partial tumor response.

The present invention further provides a method to treat a patient who has metastatic carcinoma of renal cells comprising administering to such a patient from about 4.5 micrograms / kg to about 9.0 micrograms / kg of pegylated interferon alfa-2b a once a week for a sufficient period of time to produce at least a partial tumor response.

Detailed description of the invention

The present invention provides a method improved to treat patients with RCC - especially those who They have metastatic RCC. The improved method provides a safer and more effective and tolerable treatment for RCC through the use of weekly injections of pegylated interferon alfa alone or in combination with immunotherapeutic agents such as IL-2 or fluorouracil ("5-FU"). Patients with RCC include those who have been diagnosed recently this disease as well as intolerant patients or resistant to interferon alfa. Interferon alfa treatment pegylated according to the present invention will continue for a minimum of six months and preferably for at least twelve months at unless there is clinical evidence of disease progression, unacceptable toxicity or the patient requires that the therapy.

When pegylated interferon alfa administered it is a pegylated interferon alfa-2b, the amount therapeutically effective interferon alfa-2b administered pegylated is in the range of approximately 4.5 to approximately 9.0 micrograms per kilogram of interferon Pegylated alpha-2b administered once a week (QW), preferably in the range of about 4.5 to approximately 6.5 micrograms per kilogram of interferon pegylated alpha-2b QW, more preferably in the range of about 5.5 to about 6.5 micrograms per kilogram of pegylated interferon alfa-2b QW and much more preferably in the range of about 6.0 micrograms per kilogram of interferon alfa-2b Pegylated administered QW.

When pegylated interferon alfa administered is a pegylated interferon alfa-2a, the amount therapeutically effective interferon alfa-2a administered pegylated is in the range of approximately 50 micrograms to approximately 500 micrograms once a week ("QW"), preferably about 200 micrograms at approximately 250 micrograms QW.

The expression "pegylated interferon alpha" as used herein refers to interferon conjugates alpha modified with polyethylene glycol, preferably interferon alpha-2a and -2b. The preferred conjugate of polyethylene glycol interferon alfa-2b it's PEG_ {12000} -interferon alfa 2b. The phrases "alpha interferon conjugated with polyethylene glycol weighing 12,000 molecular "and" PEG_ {12000} -IFN alpha "as used herein refer to conjugates such as that are prepared according to the methods of the Request International No. WO 95/13090 and containing urethane bonds between the amino groups of interferon alfa-2a or -2b and polyethylene glycol having an average molecular weight of 12000.

The PEG_ {12000} -interferon Preferred alpha-2b is prepared by bonding a polymer of PEG to the amino epsilon group of a lysine residue in the molecule of IFN alpha-2b. A single molecule of PEG12000 is conjugates with free amino groups in an IFN molecule alpha-2b through a urethane bond. This conjugate It is characterized by the molecular weight of bound PEG12000. He PEG_ {12000} -IFN conjugate alpha-2b is formulated as a lyophilized powder for injection. The objective of the conjugation of IFN alpha with PEG is improve protein supply significantly prolonging its plasma half-life and thus provide activity elongated IFN alpha.

The expression "interferon alfa" as used in this document it refers to the family of specific proteins of highly homologous species that inhibit viral replication and cell proliferation and modulate the immune response. The Typical suitable alpha interferons include, but are not limited to, recombinant interferon alfa-2b such as interferon Intron-A available at Schering Corporation, Kenilworth, N. J., recombinant interferon alfa-2a such as Roferon interferon available in Hoffmann-La Roche, Nutley, N. J., interferon recombinant alpha-2C such as interferon Berofor Alpha 2 available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, CT., Interferon alfa-n1, a mixture purified from natural alpha interferons such as Sumiferon available in Sumitomo, Japan or as interferon Wellferon alpha-n1 (INS) available at Glaxo-Wellcome Ltd., London, Great Britain or a consensus interferon alpha such as described in the Patents of United States No. 4,897,471 and No. 4,695,623 (especially those Examples 7, 8 or 9 thereof) and the specific product available in Amgen, Inc., Newbury Park, CA, or interferon alfa-n3, a mixture of natural alpha interferons prepared by Interferon Sciences and available at Purdue Frederick Co., Norwalk, CT. with the trade name Alferon. The use of interferon alfa-2a or alfa-2b. Since interferon alfa-2b, among all interferons, has the widest authorization worldwide to treating chronic hepatitis C infection is much more preferred. The manufacture of interferon alfa-2b is described in U.S. Patent No. 4,530,901.

Other conjugates of interferon alfa by coupling an interferon alfa to a soluble polymer in water A non-limiting list of such polymers includes other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylene polyols, copolymers of same and block copolymers thereof. As an alternative to polymers based on polyalkylene oxide, can be used in effectively form non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like. Such conjugates of interferon alpha-polymer are described in the Patent No. 4,766,106, U.S. Patent No. 4,917,888, European Patent Application No. 0 236 987, the European Patent Applications No. 0 510 356, 0 593 868 and 0 809 996 (pegylated interferon alfa-2a) and Publication International No. WO 95/13090.

The pharmaceutical composition of interferon alfa pegylated suitable for parenteral administration can be formulate with a suitable buffer, for example, Tris-HCl, acetate or phosphate such as phosphate buffer dibasic sodium / monobasic sodium phosphate and excipients (per eg, sucrose), vehicles (for example, human serum albumin),  toxicity agents (for example, NaCl), preservatives (for eg thimerosol, creosol or benzylalcohol) and surfactants (for example, pharmaceutically acceptable tween or polyisorabatos) in water Sterile for injection. Pegylated alpha interferon can be Store as lyophilized powders under refrigeration at 2-8 ° C. The Reconstituted aqueous solutions are stable when stored between 2 ° and 8 ° C and are used within 24 hours of the reconstitution. See, for example, United States Patents No. 4,492,537; 5,762,923 and 5,766,582. Aqueous solutions reconstituted can also be stored in multidose syringes preloaded, such as those useful for drug delivery such as insulin. Suitable typical syringes include systems comprising a pre-filled vial attached to a syringe of type pen such as the NOVOLET Novo Pen available in Novo Nordisk, as well as pre-filled pen syringes that They allow simple self-injection by the user. Other systems of syringe include a pen-type syringe comprising a glass cartridge containing a diluent and interferon powder Pegylated alpha lyophilized in a separate compartment.

The expression "tumor response" as used in this document refers to a reduction or elimination of All measurable lesions.

The criteria for tumor response are based on the WHO Information Criteria [WHO Offset Publication, 48-World Health Organtization, Geneva, Switzerland, (1979)]. Ideally, all measurable lesions uni- or two-dimensionally they must be able to be measured in each evaluation. When multiple lesions are present in any organ, such measurements may not be possible and, in such circumstances, if available, up to 6 must be selected representative lesions.

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The expression "complete answer" ("CR") as used in this document refers to a complete disappearance of any clinically malignant disease detectable, determined by 2 separate observations not less than 4 weeks A preliminary evaluation can be carried out with two measurements.

The expression "partial response" ("PR") as used in this document in reference to (a) Two-dimensional measurable disease refers to decrease at least about 50% of the sum of the products of the larger perpendicular diameters of all measurable lesions as determined by 2 separate observations not less than 4 weeks and (b) one-dimensional measurable disease refers to to decrease at least approximately 50% of the sum of the larger diameters of all lesions as determined by 2 separate observations not less than 4 weeks. It is not necessary to all injuries have receded to rate the response partial, but no injury should have progressed and should not No new lesions appear. You have to get evidence in series of appreciable change documented by copies of studies radiographic and has to be available for review later. The evaluation must be objective.

The expression "stable disease" ("SD") as used in this document in reference to (a) Two-dimensional measurable disease refers to less than approximately 50% decrease or less than approximately 25% increase in the sum of the products of the diameters perpendicular major of all measurable lesions and (b) One-dimensional measurable disease refers to less than approximately 50% decrease or less than approximately 25% increase in the sum of the diameters of all injuries. No new lesions should appear.

The expression "progressive disease" ("PD") as used herein refers to an increase greater than or equal to approximately 25% in the size of at least a two-dimensional measurable lesion (product of the larger perpendicular diameters) or one-dimensional or appearance of a new lesion The appearance of pleural effusion or ascites is also considered progressive disease if it Confirms by positive cytology. Pathological fracture or bone crushing is not necessarily evidence of progression of the illness.

Tumor Response in Global Subject

Determination of tumor response in subject global for measurable disease uni- and two-dimensionally it will perform according to the following table:

Subject Tumor Response Global

one

Response Evaluation in Presence of Disease No Measurable

The measurable disease will not be used in the overall subject tumor response assessment except in the following situations:

to)

Complete global response : if non-measurable disease is present, it must disappear completely. Otherwise, the subject cannot be considered a "global complete responder."

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b)

Global progression : in the case of a significant increase in the size of non-measurable disease or the appearance of a new lesion, the overall response will be progression.

The expression "patients who have carcinoma of renal cells "or" RCC "as used herein is  refers to any patient who has RCC and includes patients without prior treatment as well as patients with prior treatment as well as patients in the metastatic stage of RCC.

The term "patients without prior treatment" as used herein refers to patients with RCC.
-which include patients who have recently been diagnosed with RCC- who have never been treated with radiotherapy or any chemotherapy, for example, fluorouracil ("5-FU") or hormonal therapy or immunotherapy, for example, IL-12, as well like any interferon, including, but not limited to, interferon alfa or pegylated interferon alfa.

The expression "patients with treatment previous "as used in this document refers to patients who have initiated some form of radiation therapy or hormonal therapy or chemotherapy that includes, but is not limited to, 5 FU or immunotherapy that includes, but is not limited to, IL-2 Interleukin-2 is available under the trade name PROLEUKIN® in Chiron Corporation, Emeryville, CA 94608-3997. He fluorouracil or 5-FU is available as a solution injectable under the trade name ADRUCIL® from Pharmacia & UpjohnCo, Bridgewater, NJ 08807-12665.

The effective amount of IL-12 when used it is in the range of about 5 to approximately 20 million international units ("UI") per square meter of body surface area (m2) three times per week ("TIW") administered subcutaneously. In a preferred embodiment of the method of the present invention, the Dosage and dosage schedule for SC administration of IL-2 in combination with pegylated interferon alfa it will be approximately 20 million IU / m2 TIW in the first week and every four weeks after this and about 5 million IU / m2 TIW in subsequent weeks of treatment, by For example, weeks 2, 3, 5, 6, 7, 9, 10, 11 and following.

The effective amount of 5-FU when used it is in the range of approximately 12 mg / kg / day IV (should not exceed 800 mg) for 5 days. If it has not taken place toxicity, 6 mg / kg / day IV on days 7, 9, 11 and 13. To maintenance, if the toxicity for the first cycle is minimal, repeat the cycle every 30 days or give 10 to 15 mg / kg (do not exceed 1 g) once a week, after the recovery of toxicity Initial is complete. These doses can be reduced by the doctor depending on the severity of the disease and the condition of the patient and the reaction to pegylated interferon alfa. An infusion constant with an implantable pump can be more effective and less toxic than periodic injections in embolada.

Pegylated interferon alpha formulations they are not effective when administered orally, so that the preferred method of administration of interferon alfa Pegylated is parenterally, preferably by injection subcutaneous, IV or IM. Of course other types of administration of both medications as soon as they are available, such as by nasal spray, transdermally, by suppository, by sustained release dosage form and by pulmonary inhalation. Any form of administration It will work as long as the appropriate dosages are supplied without destroying the active ingredient.

The following Study Design can be used Clinic to treat patients with RCC according to the method of The present invention. Many modifications to this protocol Clinical Study Design will be obvious to the specialist doctor and the following Study Design should not be interpreted as limiting the scope of the method of this invention that is defined by the claims indicated later in this document.

Clinical Study Design

In a preferred embodiment of the method of Treatment of the present invention, subjects with metastatic RCC they will receive pegylated interferon alfa 2b, that is, PEG_ {12000} -interferon alfa 2b at a dose of 6.0 micrograms per kilogram per subcutaneous injection once per week.

Study Duration and Consultation Program

The duration of this study is based on getting a therapeutic response and will be determined individually to each subject

Treatment with PEG Intron will continue for a minimum of 6 months unless there is evidence of progression of disease, unacceptable toxicity or the subject requires that discontinue therapy The tumor response will be evaluated starting week 8, will be evaluated every 8 weeks after this during the First year of study treatment. The population pharmacokinetics at various times throughout the study. In addition, quality of life data will be collected and global survival Subjects who get a response from complete or partial tumor at 6 months will continue treatment for another 6 months.

The following clinical protocol can be used To administer the RCC therapy of the present invention:

The study population will include patients male and female with metastatic RCC and will be included if they meet  The following inclusion and exclusion criteria:

Subject Inclusion Criteria

A subject meets the requirements to participate in this study if he or she:

to)

have documented metastatic renal cell carcinoma histologically

b)

have an ECOG General Status of 0 or 1.

C)

have ? 18 and? 70 years old.

d)

have a life expectancy of> 8 weeks.

and)

have adequate final organ function (hepatic, renal, bone marrow, cardiac), as indicated by the following values of laboratory:

one) Hematology:

-

Absolute Neutrophil Count (RAN) ≥ 3,000 cells / mul.

-

Platelet count ≥ 100,000 cells / µl.

-

Hemoglobin concentration ≥ 9 g / dl

2) renal function and liver:

-

Serum creatinine ≤ 1.8 mg / dl or creatinine clearance calculated from ≥ 50 ml / minute

-

Serum bilirubin ≤ 1.25 times the upper limit of normal (LSN), unless due to disease infiltration.

-

AST / ALT (SGOT / SGPT) ≤ 1.25 times LSN, unless due to disease infiltration.

-

Ag of HB negative.

3) Calcium normal plasma

F)

be there sent a voluntary informed consent in writing before entry into the study, want to participate in this study and Complete all follow-up evaluations.

Subject Exclusion Criteria

A subject does not meet the requirements for Participate in this study if he or she:

to)

he has received any previous non-surgical treatment for RCC, including chemotherapy, complementary chemotherapy, immunotherapy, radiotherapy or hormonal therapy.

b)

have evidence of CNS metastases.

C)

have a known hypersensitivity to interferonα.

d)

have a serious cardiovascular disease, that is, arrhythmias that require chronic treatment or congestive heart failure (NYHA classification III or IV).

and)

have a history of neuropsychiatric disorder that requires hospitalization.

F)

have a history of seizure disorder

g)

have Thyroid dysfunction that does not respond to therapy.

h)

have uncontrolled diabetes mellitus

i)

have a second active neoplasm with risk to life.

j)

have an active infection in progress that requires antibiotics.

k)

requires chronic treatment with systemic corticosteroids

l)

have a history of HIV seropositivity.

m)

is pregnant, nursing or at risk of becoming pregnant and does not practice any effective means of contraception.

n)

have active hepatitis

or)

be known to actively abuse alcohol or drugs.

p)

he has received any experimental therapy in the interval of 30 days to entry into this study and

q)

I dont know He has recovered from the effects of any recent surgery.

Subject Abandonment Criteria

It is the right and duty of the investigator clinical interrupt the treatment of any subject whose health or welfare can be put at risk by continuing in this study.

A subject can be excluded before the Completion of the study if he or she:

to)

have a clinically significant adverse event as determined by the principal investigator.

b)

need to be removed from study.

C)

is unable to answer the study evaluations / queries due to unforeseen circumstances.

d)

develops other conditions for that, in the opinion of the researcher, it is in the interest of the subject to be withdrawn from the study.

and)

develops severe depression or any another psychiatric disorder that requires hospitalization.

F)

experience an allergic response severe to the study drug manifested by angioedema, bronchoconstriction or anaphylaxis.

Other Clinical Study Design

In another preferred embodiment of the method of Treatment of the present invention, subjects with RCC metastatic will receive pegylated interferon alfa 2b, that is, PEG_ {12000} -interferon alfa 2b at a dose of 6.0 micrograms per kilogram per subcutaneous injection once per week in combination with SC administration of IL-2 according to the following guideline: 20 million IU of IL-2 / m2 TIW at week 1 and every fourth week  after this and 5 million IU of IL-2 / m2 TIW in weeks 2, 3, 5, 6, 7, 9, 10, 11 and following.

Analysis of Primary and Secondary Assessment Criteria

The primary efficacy assessment criterion It will be the tumor response at 6 months. The primary analysis will be the comparison of treatment groups with respect to the proportion of subjects with main tumor response at 6 months using the Cochran Mantel-Haenszel test with adjustment for strata. The odds ratio and intervals will be summarized 95% confidence for the odds ratio.

The secondary assessment criteria of the study will be survival without relapse at 3, 6 and 12 months and global survival Survival without relapse and overall survival will be analyzed using rank statistics logarithmic Estimates of are provided Kaplan-Meier of survival curves. Be they will obtain the risk ratio and the 95% confidence interval of the risk ratio using the proportional risk model of Cox

Claims (13)

1. The use of interferon alfa-2b Pegylated for the manufacture of a medicament for treatment of a patient who has renal cell carcinoma, in which said medication must be administered in one dose therapeutically effective interferon alfa-2b pegylated once a week for a period of at least 12 months, in which pegylated interferon alfa-2b comprises polyethylene glycol having an average molecular weight of 12,000 and the therapeutically effective dose of approximately 4.5 \ mug / kg at about 9.0 \ mug / kg. 2. The use according to claim 1, in that the therapeutically effective dose is in the range of about 5.5 µg / kg to about 6.5 µg / kg. 3. The use according to claim 1, wherein the therapeutically effective dose is approximately
6.0 µg / kg. 4. The use according to the claims 1-3, in which said medication must be administer in therapeutically effective dose once a week for a period of time sufficient to produce at least one partial tumor response. 5. The use according to the claims 1-4, in which said medication must be administer in combination with subcutaneous administration of interleukin-2 (IL-2) in a amount of about 5 to about 20 million international units (IU) per square meter of area of body surface area (m2) three times a week (TIW). 6. The use according to claim 5, in the one that the dosage and the dosage schedule for the IL-2 administration will be approximately 20 million IU / m2 TIW in the first week and every fourth week after this and approximately 5 million IU / m2 TIW in the subsequent weeks of treatment. 7. The use according to the claims 1-4, in which said medication must be administered in combination with intravenous administration of fluorouracil (5-FU) in an amount of approximately 12 mg / kg / day for 5 days. 8. The use according to claim 7, which also includes intravenous administration of 6 mg / kg / day of 5-Fu on days 7, 9, 11 and 13. 9. The use according to the claims 1-8, in which interferon alfa-2b Pegylated is formulated as a lyophilized powder for injection. 10. The use according to the claims 1-9, in which the patient is a is a patient without previous treatment. 11. The use according to the claims 1-9, in which the patient is a patient with pretreatment that is intolerant of interferon alfa or interferon resistant alpha. 12. The use according to the claims 4-11, in which the tumor response is a complete tumor response 13. The use according to the claims 1-12, in which renal cell carcinoma is metastatic renal cell carcinoma.